Collaborative Research: MODULUS: Copy Number Alterations and Xenobiotic adaptation

理解进化是理解地球上生命的基础。进化也给人类健康带来了一些最大的挑战。病毒、细菌、真菌和癌细胞都会对外源物质产生抗药性。这些外来生物是不是自然发现的分子，但会影响自然界的进化。该项目旨在创造新的理论和实验来了解异种生物的进化。该项目的成果将在许多不同的领域得到应用，例如抗药性细菌、抗药性疟疾寄生虫、抗药性抗癌药物的肿瘤细胞、抗药性除草剂的植物和抗药性的昆虫。该奖项为培养STEM研究生提供支持，这些研究生最终将成为劳动力的一部分。该项目还为本科生提供了研究机会，并开发了新的教育游戏，以外来生物进化为例，向K-12学生传授科学知识。该项目的主要目标是发现突变和基因放大之间相互作用导致的外来生物适应的新方面。该项目在利福平诱导的大肠杆菌抗生素耐药性进化的背景下，研究了导致异种适应的复杂、非线性的进化途径。在数学上，该项目将通过使用一个随机过程来将抗性进化建模为质粒拷贝数的函数，该随机过程解释了正在进化的细胞群落的隧道率和空间结构。该项目利用了一个不连贯的前馈环路，在保持生化水平恒定的同时，给出了提供细胞内质粒拷贝数变化的综合控制。合成生物学实验的设计旨在将正在开发的模型参数化，并探索模型所指示的重要特定参数的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding evolution is fundamental to understanding life on earth. Evolution also creates some of the greatest challenges to human health. Viruses, bacteria, fungi, and cancer cells all evolve resistance to xenobiotics. These xenobiotics are molecules that are not found naturally but that influence evolution in the natural world. This project aims to create new theory and experiments to understand xenobiotic evolution. The results of this project would have applications across many different fields such as bacteria resistant to antibiotics, malaria parasites resistant to antimalarial drugs, tumor cells resistant to cancer drugs, plants resistant to herbicides, and insects resistant to insecticides. The award provides support to train STEM graduate students that will eventually become part of the workforce. The project also provides research opportunities for undergraduates and develops new educational games that teach K-12 students about science, using xenobiotic evolution as an example.The main goal of this project is to discover novel aspects of xenobiotic adaptation that result from the interactions between mutations and gene amplifications. The project examines the complex, nonlinear evolutionary pathways that lead to xenobiotic adaptation in the context of antibiotic resistance evolution induced by Rifampin in E. coli. Mathematically, the project would model resistance evolution as a function of plasmid copy number with the use of a stochastic process that accounts for tunneling rates and spatial structures of the community of evolving cells. The project makes use of an incoherent feed forward loop that gives synthetic control for providing variation in plasmid copy numbers in cells while keeping biochemical levels constant. Synthetic biology experiments are designed with a view to parametrizing the models under development and exploring the effects of specific parameters that have been indicated as important by the model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.